Adoptive transfer of antigen-specific CD4⁺ and CD8⁺ T cells is one of the most efficient forms of cancer immunotherapy. However, the isolation of antigen-specific CD4⁺ T cells is limited because only few tumor-associated helper epitopes are identified. Here, we used T cell antigen receptor gene transfer to target CD4⁺ T cells against an MHC class I-presented epitope of a model tumor antigen. IFN-γ-producing CD4⁺ T cells were unable to expand in vivo and to provide help for tumor rejection. In contrast, CD4⁺ T cells producing high levels of IL-2 expanded in vivo, provided help for cytotoxic T lymphocyte-mediated tumor rejection, and developed T cell memory. The data demonstrate in vivo synergy between T cell antigen receptor-transduced CD4⁺ and CD8⁺ T cells specific for the same epitope resulting in long-term tumor protection.